Intestinal disease is an important cause of economic loss in the sheep and rabbit industries, and the part played by coccidia is difficult to define. This study was to improve our understanding of how coccidia cause disease, how this disease can be diagnosed and how immunity to it is acquired. Infections with known numbers of known coccidial species were given to coccidia-free lambs and rabbits. Clinical (and in some cases haematological) data and oocyst output were recorded. Animals were killed at different intervals after infection, and their tissues examined by light microscopy and by transmission scanning electron microscopy. Studies were also made in field lambs on active and passive immunity and on oocyst output in relation to clinical signs. Eimevia flavescens in rabbits and E. ovinoidalis in lambs are reputed to be highly pathogenic. They were found to share some features of their life-cycle not shared by less harmful species. Gametocytes were the most harmful stage; these infected cells of the caecal crypts, including stem cells at the crypt bases. If large numbers of gametocytes were involved, crypt cells were eliminated over large areas of caecum, leaving the mucosa denuded and depleted of regenerative capacity. Less pathogenic species such as E. irresidua in rabbits and E. ovina in lambs appeared to favour the superficial epithalial cells leaving the crypt cells to restore the epithelial covering rapidly after the coccidia had passed. Z. ovina appeared sometimes to stimulate proliferation of host enterocytes, causing polyp formation. The susceptibility of lambs appeared to be modified by both active and passive immunity. Tine factors appeared to interact in a complex way with each other arid with incoming coccidia, which suggested a need for much further research. Oocyst output was of little value as an indicator of the tiptake of coccidia or of the part played by them in the aetiology of intestinal disease.

Fetal gene therapy may treat genetic diseases before significant organ damage, target stem cell populations and avoid immune sensitisation. Candidate diseases include cystic fibrosis, haemophilia and lysosomal storage disorders. This thesis developed ultrasound-guided delivery of viral vectors to the sheep fetus for treatment of these diseases. For haemophilia B treatment we delivered adenovirus vectors containing the p-galactosidase reporter gene (adlacZ) or the human factor IX gene (adhFIX) by ultrasound guidance to the early gestation sheep fetus, when it is considered to be pre-immune. Intraperitoneal injection allowed the earliest time point for gene delivery, achieved the highest hFIX levels and the most localised p-galactosidase expression. Therapeutic hFIX levels were detected after intramuscular and intra-amniotic delivery suggesting that these are potentially alternative sites for therapeutic gene expression. For each route examined, no humoral immune response was observed to the transgene, although antibodies to the adenovirus vector were identified. We achieved intravascular delivery via umbilical vein injection therapeutic hFIX levels were detected. We developed ultrasound-guided transthoracic injection of the mid-gestation fetal trachea for cystic fibrosis treatment, p-galactosidase expression, measured by ELISA, was low after delivery of adlacZ vector alone, but increased 10 fold when the vector was complexed with DEAE dextran. Pretreatment of the fetal airways with sodium caprate increased expression by 90 fold the effect of the two agents was synergistic. Perflubron instillation following vector injection redistributed transgene expression from the large to the small airways. We developed ultrasound-guided fetal intragastric injection and achieved widespread transgene expression throughout the gastrointestinal epithelia after adlacZ vector delivery. For brain manifestation of lysosomal storage disorders we injected adlacZ vectors to the fetal ventricles under ultrasound guidance. Transduction of the choroid plexus was seen. Future application of integrating vectors such as lentivirus may allow for long term therapeutic correction and induce immune tolerance to the transgene.

This thesis aims to investigate the prevalence and control of both endoparasites and ectoparasites of sheep and the prevalence of anthelmintic resistance on sheep farms in Northern Ireland via a unique approach involving on farm, face-to-face interviews and sampling, rather than a more common hands off postal survey. Analysis of faecal samples and producers' own records revealed that sheep across the province are subject to infection by a range of parasite species including; nematodes, Nematodirus spp., Trichostrongylus spp., Teladorsagia circumcincta, Haemonchus contortus, Cooperia spp., Capillaria spp., Strongyloides spp., trematode, Fasciola hepatica, cestode, Moniezia expansa, arthropod, Bovicola ovis, Psoroptes ovis, Ixodes ricinus, Oestrus ovis, Lucillia spp. and Calliphora spp. Questionnaire data revealed that the majority of producers are not fully aware of the impacts of clinical, sub clinical infections or anthelmintic resistance and none had attempted to perform any form of cost-benefit analysis to assess the impact of infection or success of a control strategy. Despite user-friendly guidelines sustainable parasite control being available, control within the N.!. sheep industry is broadly based on regular prophylactic blanket treatments incorporating ineffective treatments such as inaccurate dosing per weight and inappropriate drug/chemical choice. Not only are these practices ineffective at controlling the parasite population already present but they also drive selection pressure towards the development and proliferation of resistant alleles in future generations. An investigation of the anthelmintic resistance status of the study farms via faecal egg count reduction testing and egg hatch assays has shown single and multidrug anthelmintic resistance to be commonplace. Overall this study highlights that a drastic shift in flock health management must occur if the sheep industry is to remain economically viable. This can only be achieved by better awareness and application of best practice guidelines and cooperation between farmers, vets and researchers.

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